Substituted pyrroles



United States F 2,901,439 SUBSTITUTED 'PYRRoLEs N Drawing.

This invention relates to new. organic compounds. More particularly, itrelates to acylaminopyrroles.

. The new compounds of the present invention can be illustrated by thefollowing general formula:

x-NrromG-NH R.

a N E-z in which R R and R are members of the group consisting ofhydrogen and lower alkyl radicals, X is a member of the group consistingof hydrogen and an amidino radical, and Z is a member of thegroupconsisting of lower alk'oxy, amino, and omega-carbamoyl loweralkylamino radicals and salts thereof. The present compounds are usuallycrystalline in structure and often have relatively high melting points.The salts, in general, are insoluble in organic solvents and relativelysoluble in water. .j f

The compounds of the present invention, in general, are prepared by amethod which includes the removal of the carbobenzoxy group from thecorresponding carbobenzoxy (amino-acetamido)pyrroles. r

This reaction can be illustrated by the following equation: Y

o 0 -on,ot mnornlinn Bi o -0H.R mNombNH R. co,

- Rs] N [0-2 I is R:

ing point 267 -268 C. (dec.)

2,901,489 Patented Aug. 25, 1959 ice alytic hydrogenation at roomtemperature using a catalyst such as palladium. The second method iscleavage using a solution of anhydrous hydrogen bromide in glacialacetic acid. Following removal of the carbobenzoxy group, the(aminoacetamido)-pyrrole can be reacted with cyanamide or otherguanylating agents to produce the corresponding(guanidinoacetamido)-pyrrole, which is also described in the exampleshereinafter.

The starting material for the compounds of the present invention can beprepared by the addition of an alkyl chlorocarbonate to a solution oftriethylamine and carbobenzoxyglycine in an inert solvent. Thecombination of the latter two compounds produces a triethylamine salt,which reacts with the alkyl chlorocarbonate to form a reactive mixedcarbonic anhydride and triethylamine hydrochloride. The anhydride isthen treated with an aminopyrrole and the desired intermediate purifiedby means well known to those skilled in the art.

The compounds of the present invention inhibit the growth of bacteriaand fungi. For example, they are effective against mycobacterium S.P.607, Sarcina lutea, Horm-odendrum cladosporoides, streptococcus at 1mg./ ml. or less. They are, therefore, useful as antibacterial agents orantifungal agents. They can be used as a dusting powder or in solution.7,

The following examples illustrate the preparation of the compounds ofthe present invention in greater oarticularity.

Example 1 A mixture of 2.0 g. (5.0 millimoles)beta-[4-(carbobenzoxyaminoacetamido) 1 methyl 2 pyrrolecarboxamido]-propiona mide, 1.0 g. 10% palladium or charcoal catalyst, 1 ml. water,and 50 ml. methyl alcohol was shaken under an atmosphere of hydrogen inthe Pan low pressure apparatus during one-half hour. The mixture wasfiltered, and the filtrate was treated with 1 ml. glacial acetic acidand concentrated on the steam bath at atmospheric pressure to leave ayellow glass. This was dissolved in 10 ml. hot ethyl alcohol and allowedto cool.

The solid that separated was collected by filtration and dried' to give1.5g. pale yellow solid, melting point 173- 176 C. Recrystallizationfrom ethyl alcohol gave beta- [4 (arninoacetamido) 1 methyl 2pyrrolecarbox- 'amidol-propionamide acetate, 21 white solid, meltingpoint 175-177 C.

Analysis.-Calcd. for C11H1'7N5O3.HC2H3O2I C, 47.7; H, 6.55; N, 21.4.Found: C, 46.9; H, 6.44; N, 21.1.

Example 2 A solution of 2.0 g. (5.6 millimoles) ethyl4-(carbobenzoxyaminoacetamido) 1 methyl 2 pyrrolecarboxylate in ml.glacial acetic acid saturated with dry hydrogen bromide was allowed tostand four hours at room temperature. Anhydrous ether (100 ml.) wasadded, and the mixture was chilled. The precipitated solid was collectedby filtration and dried to give 1.0 g. white solid, melting point 266.0267.5 C. (dec.) darkening from 250 C. Recrystallization from aceticacidether gave white crystals of ethyl 4-(aminoacetamido)- 1 methyl 2pyrrolecarboxylate hydrobromide, melt- Analysis.Calcd. forC10H15N303-HB1'! C, H, 5.26;.N, 13.7. Found: C, 39.1; H, 5.35; N, 13.7.

Example 3 The following compounds were prepared by the method of Example2:

Analysis Recrystallization Percent Meltln Name Empirical Formula SolventYield Point O H N Calcd. Found Calcd. Found Calcd. FoundA-(aminoacetamido)-2-pyr- C1H1uN4O2.HB1 Acetone-water 87 300-302 31.931.9 4. 22 4.44 21.3 21.2

' ll'lole-ciaboxamme hydro- (dec.)

tom e. l

,drobromlde.

Ethyl 4-(aminoacetamidoy C17H13N:O3.HBI Water 69 296-297 43.1 42.9 6.005.85 12.6 12.4

1,3;-tr1methyl-Z-pyrrole- -(d'c.)' g i carhoxylate hydrobromide.

t i wt yl- CBH12N4O2.HBI'. Methanol-ether... 204-265 82.5 32.3 5.04 5.0619.0 19 3 2-py1ro1ecarhoxamide hy- H2O (dec.) drobromlde.

El: 'yl 1-(aminoacetaruido)- CpH 3N O .HBr do 93 224.5-226.0 87.0 37.24. 83 4. 91 14.4 14.2

-pyrmlecarhoxylate hy- (dec.)

- drobromide.

Example 4 water was buffered to pH 8.8 with concentrated aqueous Asuspension of 3.0 g. (0.010 mole) ethyl 4-(amino- 25acetamido)-1-methyl-2-pyrrolecarboxylate hydrobromide and 5.0 g. (0.030mole) 25% aqueous cyanamide in 5 ml. water was buifered to pH 8.7 withconcentrated aqueous ammonia. The resulting yellow solution was allowedto stand at room temperature for 7 /2 days. At the end of this time somesolid had precipitated from the now dark-brown solution. The solvent wasremoved in a current of air, and the residue was triturated with 5acetone, removed by filtration, and dried to give 2.3 g. (63%) yield tansolid, melting point 189193 C. (dec.). Purification by dissolution inmethanol, clarification with activated charcoal, filtration, chilling,and dilution with anhydrous ether gave ethyl 4-(guani'dino'-acetamido)-l-methyl-2-pyrrolecarboxylate hydrohromide as a white solid,melting point 199-20l C. (dec.). Analysis.-Calcd. for C H N O l-IBr: C,37.9; H, 5.20; Br, 23.0; N, 20.1. Found: C, 38.2; H, 5.35; Br, 23.1; N,20.2. This material formed a yellow picrate, melting point 21-6.02l7.5C. (dec.).

Analysis.--Calcd. for C11H17N5O3.C6H3N3O7I C, 41.1; H, 4.07; N, 22.6.Found: C, 40.9; H, 4.13; N, 22.4.

Example 5 A solution of 1.0 g. (3.3 millimoles) ethyl4-(aminoacetamido-Z-pyrrolecarboxylate hydrobromide and 1.0 g. 6.0millimoles) 25% aqueous cyanamide in 3 ml. water was buttered to pH 8.8with concentrated ammonium hydroxide solution and. allowed to stand sixdays at room temperature. The dark solution was clarifled with.activated charcoal, and the resulting pale-yellow solution was taken toan oily residue under reduced pressure on the steam bath. The residuewas triturated with ethanol, and the solid removed by filtration. Thealcohol was removed from the filtrate to give ethyl-4-(guanidino-'acetamido)-2py1roleca.rboxylate hydrobromide as an oil.

Example 6 A solution of 0.50 g. (1.5 millimoles)beta-[4-(aminoacetamido)-1 methyl 2 pyrrolecarboxamido]-propionamideacetate and 1.0 g. (6.0 millimole) 25% aqueous cyanamide in 2 ml. waterwas buffered to pH 8.7 with concentrated ammonium hydroxide and allowedto stand for eight days. Removal of the water gave beta-[ 4-(guanidinoacetamido)-1-methyl-2 pyrrolecarboxamidolpropionamide acetate.7.0

Example 7 A solution of 500 mgm. (1.90 millimoles) 4-aminoacetamido)-2-pyrrolecarboxamide. hydrobrornide and 1.0 g. (6.0millimoles)-25% aqueous cyanamide i112 ml.

ammonia andallowed tov stand five days at room temperature. The solutionwas concentrated in. a current of air to give a dark residue, which wasdissolved in 20 ml. methanol, .decolorized activated charcoal, andfiltered. The filtrate was treated with picric acid to give 30 200 mgms.of 4-(guanidinoacetami'do)-2-pyrro1ecarboxamide picrate, orangecrystals, melting point greater than 240 C. after recrystallization fromdilute alcohol.

Analysis.CalC d. C H N O .C H N O C, H, 3.33; N, 27.8. Found: C, 36.5;H, 3.46; N, 27.7.

suspension of 140:.mgms. (0.42 millimole) ethyl 4- (aminoacctamiidol-l,3,5-.trimethyl 2-pyrrolecarboxylate hydrobromideand 0.5 g. (3 millimoles)25% aqueous cyanamide in 2' ml. water was adjusted to pH 8.8 withconcentrated aqueous ammonia. Most of the solid dissolved, andthemixture was allowed to stand atroom temperature for 11 days. Thesolid was collected. by filtration and dried to give mgms. ethyl 4-(guanidinoacetamido) -l ,3 .,5-trirnethyl.-2 -'pyrrolecarboxyla tehydrohromide, a solid. melting at l-.83187 C. (dec.).

A portion of this solid was treated with aqueous picric acid and gave ayellow pi'crate, melting point 212-215 C. (dec) and-darkening from 205C.' A mixture with the picrate described in the following example showedidentical melting point behavior.

Example 9 A solution of 2.53 g. (0.010 mole) ethyl4-(aminoacetami'do)-1,3,S-trimethyl-Z-pyrrolecarboxylate in 10 ml. waterwas treated with 2.0 g. (0.010 mole) l-guanyl- 3,5-dimethylpyrazo'lenitrate in 10 ml. water. The solution was allowed to reflux during 24hours. The solution was extracted with ether and then concentrated in acurrent of to. ca. one-half volume. ,T-he solid that separated wascollected by filtration and recrystallized from methanol-ether tog-ive2.5 g. (67% yield) of ethyl 4- (guanidinoacetamido)-1,3,5 trirnethyl2-pyrrolecarboxylate nitrate hydrate as a white solid, melting pointl68170 C.

AWZYSiSr-CZJJQd. for C13H31N5Q3.HNO3.H2O1 C, 41.6; H, 6,44; N, 22.3; E0, 4.78. Found: C, 42.0; H, 6.11; N, 22.3; H 0, 4.71. Upon treatmentwith picric acid, this material furnisheda yellow picrate, melting point21309-2155? C. (dec.), which darkened from 207 C.

' Example 10 A mam-1.96 (0.010m1ole) 4-(aminoacetamido)--1:-methy1-2-pyrrolecar5oxamide in 15 ml: methanol. was

allowed to reflux with 2.0 g. (0.010 mole) 1-guany1-3,5-dimethylpyrazole nitrate in ml. water for 21 hours. The solution wasconcentrated to ca. 7 ml. in a current of air, diluted to ca. 20 ml.with water, and thrice extracted with 20 ml. ether. The aqueous phasewas concentrated to a viscous orange oil in a current of air.Trituration with hot methanol caused the oil to crystallize. The hotmixture was chilled and filtered to give a tan solid,4-(guanidinoacetamido)-1-methyl-2-pyrro1ecarboxarnide nitrate hydrate,melting point 127 -132 C. Two recrystallizations from methanol etherwater (:30:1) gave 500 mgm. of white crystals, melting point 142144 C.after sintering at 60 C.

Analysis.-Calcd for C H N O -HNO H O: C, 33.9; H, 5.36; N, 30.4; H O,5.65. Found: C, 33.7; H, 5.44; N, 30.6; H O, 5.46.

We claim:

1. A compound selected from the group consisting of those having theformula X--NHCHzC-NH R;

R [Cl-Z in which R R and R are members of the group consisting ofhydrogen and lower alkyl radicals, X is a member of the group consistingof hydrogen and the amidino radical, and Z is a member of the groupconsisting of lower alkoxy, amino, and omega-carbamoyl lower-alkyl aminoradicals and acid addition salts of the group consisting of acetate,hydrobromide, picrate, and nitrate salts.

2. A lower alkyl 4-aminoacetamido)-1,3,5-triloweralkyl-Z-pyrrolecarboxylate acid addition salt of the group consisting ofacetate, hydrobromide, picrate, and nitrate salts.

3. A lower alkyl 4-(guanidinoacetamido)-1-1ower alkyl2-pyrrolecarboxylate acid addition salt of the group consisting ofacetate, hydrobromide, picrate, and nitrate salts.

4. Ethyl 4-(aminoacetamido)-1,3,5-trimethyl 2 pyrrolecarboxylatehydrobromide.

5. Ethyl 4 (aminoacetamido)-1-methy1-2-pyrrolecarboxylate hydrobromide.

6. Ethyl 4 (guanidionacetamido) -1-methy1-2-pyrrolecarboxylatehydrobromide.

7. 4-(guanidinoacetamido) 1 methyl 2 pyrrolecarboxamide nitrate hydrate.

8. 4-(guanidinoacetamido) 2 pyrrolecarboxamide hydrobromide.

References Cited in the file of this patent UNITED STATES PATENTS2,785,181 Waller et a1 Mar. 12, 1957 2,785,182 Waller et a1. Mar. 12,1957 2,785,183 Waller et a1. Mar. 12, 1957 2,797,228 Webb et a1. June25, 1957

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THEFORMULA